Human C5a anaphylatoxin is a low molecular weight glycopolypeptide released from the fifth component of complement during complement activation. This factor is a potent mediator of several neutrophil responses including: chemotaxis, lysosomal enzyme release, autoaggregation and superoxide production. Studies conducted with 125I-labeled C5a serving as a ligand probe have demonstrated that these cellular responses follow binding of C5a to a specific neutrophil receptor. We propose to investigate the in vitro responses of both human and rabbit peripheral blood neutrophils to human C5a and selected analogs of this factor. By quantitatively defining the biological activities of these polypeptides it will be possible to define the relative activity of each factor. In addition, by performing sensitive 125I-labeled ligand binding studies it will be possible to accurately detect C5a structural analogs that lack intrinsic biological activity yet retain the capacity for receptor interaction. Clearly, derivatives that possess these particular characteristics may act as antagonists of C5a-mediated cellular responses and will be tested for this particular property. Similar assessments of C5a-related activity will be carried out in vivo by measuring the degree of neutropenia induced by these factors following their infusion into rabbits. Structural analogs of C5a that have been shown to act as antagonists in in vitro assays will also be examined to determine if they retain these properties in vivo. These investigations will not only increase our understanding of the nature of C5a-receptor interactions at the molecular level, but will also contribute significantly toward defining the role of this potent mediator in the acute inflammatory response. It is possible that such studies may permit development of agents that selectively modulate neutrophil function in pathologic states.